Describing Orlando would be a very difficult task, as it represents many different forms for many people. From a manicured landscape devoid of interest, to a land where everything is possible (including entering houses upside down); from a place where hectic meetings are held, to the site of Disney World where child fantasies are realized. Not for everybody, but a dreamland for many! However, if sweet is one of the adjectives that may be used to describe the greater Orlando area, sweet, at least sweet food, is one of the enemies of diabetes, and Orlando is also a place where food is available, but is not particularly healthy. Fat and sugar galore! Obviously strategies to prevent and treat diabetes have been and continue to be intensely researched, although not always feasible. The finding that the prevalence of diabetes is lower in marijuana users [Rajavashisth, T.B. et al., Abst 659-P], for example, does not open a feasible strategy for preventing diabetes, but does suggest targets and opens research avenues that may eventually result in clinically relevant findings.

Although without preventing the loss of C-peptide and without a negative impact on the quality of life [Nishigaki, Y. et al., Abst 1973-P], insulin is a major asset in the treatment of diabetes and the control of glycemia [Badaru, A. et al., Abst 1908-P], despite the increased risk for macrosomia when used as continuous subcutaneous infusion to manage gestational diabetes [Skalli, S. et al., Abst 121-LB]. A number of recombinant products, formulations and analogous have been developed. However, besides hypoglycemia, excessive doses of insulin may also result in cardiac conduction defects leading to serious, even life-threatening arrhythmias [Yagi, K. et al., Abst 682-P]. In addition, recombinant human insulin resulted in similar control of hemoglobin A1c in patients with type 2 diabetes, compared to regular human insulin [Rodbard, H.W. et al., Abst 36-OR].

Metformin has long been used in the treatment of diabetes, and is still the background agent for many antidiabetic combinations, although responses to the agent were improved in younger male patients with lower body mass index [Wang, C.P., Abst 709-P]. Besides improving glycemia in diabetes, metformin also prevented hepatocellular carcinoma in patients with cirrhotic hepatitis C [Cosson, E. et al., Abst 1089-P]. Mechanistically, treatment with metformin was related to improvement in leukocyte inflammation and senescence through an effect on the sirtuin-7 pathway [Zeng, W. et al., Abst 882-P], while the agent was reported to prevent calcium-induced opening of the mitochondrial permeability transition pore in obese animal models [Lin, C.T. et al., Abst 1603-P]. Metformin has been associated with tolerability issues that, according to new data discussed in Orlando, have been overcome by a gastro-retentive formulation that was well tolerated in patients previously intolerant to the standard formulation [Sweeney, M. et al., Abst 729-P]. Furthermore, the addition of thiazolidinediones, sulfonylureas and glinides to metformin was noted to be associated with increased body weight, whereas metformin combined with incretin mimetics, a-glucosidase inhibitors or dipeptidylpeptidase-4 inhibitors was neutral or resulted in weight loss [Phung, O.J. et al., Abst 567-P].

A combination of metformin and colesevelam was at least as effective as metformin, but resulted in an improved tolerability profile with a marked reduction in metformin-related diarrhea, offering a safe option for first-line treatment of hypercholesterolemic diabetes [Abby, S.L. et al., Abst 633-P]. Furthermore, colesevelam was associated with increased levels of glucagon-like polypeptide-1, helping restore the incretin effect in type 1 diabetes [Ritchie, P.J. et al., Abst 808-P]. In the experimental setting, metformin was demonstrated to stimulate glucagon-like peptide-1 production by intestinal L-cells through an effect on Wnt signaling [Kim, M.H. et al., Abst 278-OR]. In addition, although without being potent inhibitors of the apical sodium-dependent bile acid transporter, both metformin and phenformin increased bile acid content in the intestine, an effect that contributes to the glucose-lowering activity of these biguanides [Yao, X. et al., Abst 611-P].

Glucagon-like polypeptide-1 analogues have been developed as a treatment for diabetes, with activity against oxidative stress comparable to biguanides and thiazolidinediones although through different mechanism of action (transactivation of the epithelial growth factor receptor/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin/GCL signaling, inhibition of permeability transition pore opening and upregulation of Bcl-2, respectively), all of which offer promise for treating and preventing diabetic encephalopathy [Okouchi, M. et al., Abst 662-P].

Furthermore, studies with exenatide indicated protection against glucocorticosteroid-induced glucose intolerance and islet cell-dysfunction [Van Raalte, D.H. et al., Abst 233-OR]. Exenatide was also tested in combination with metformin, resulting in increased rates of glycemic control [Riddle, M. et al., Abst 18-LB], and in combination with pioglitazone, resulting in improved glycemic control and b-cell function without the weight gain observed with pioglitazone alone [Chavez, A.O. et al., Abst 320-OR; Chavez, A.O. et al., Abst 744-P]. Note that improvements in b-cell disposition index gained with long-term exenatide were maintained for at least four weeks after discontinuation [Bunck, M.C. et al., Abst 728-P]. In experimental studies, treatment with the agent prevented b-cell apoptosis through an effect on the protein kinase A/phosphatidylinositol 3-kinase pathway [Wang, L. et al., Abst 1673-P], and also protected the cells against amyloid peptide-induced damage through an effect on the Akt pathway and mitochondrial biogenesis [Fan, R. et al., Abst 1674-P; Aston-Mourney, K. et al., Abst 1677-P] (note that protection against amyloid-induced b-cell apoptosis resulted also from treatment with a peptide Jun kinase inhibitor [Subramanian, S.L. et al., Abst 1675-P]), and against sulfonylurea-induced apoptosis through an effect on calcium-dependent endoplasmic reticulum stress [Kim, J.Y. et al., Abst 1678-P]. An important observation related to exenatide came from a simulated comparison versus intensive therapy with traditional therapies, according to which the incidence of cardiovascular morbidity and mortality was reduced by the incretin mimetic, which was also associated with better protection against diabetic neuropathy and nephropathy [Peskin, B.R. et al., Abst 592-P]. On the other hand, chart and claim reviews did not demonstrate any association between use of exenatide and an increased risk of acute pancreatitis [Bloomgren, G. et al., Abst 543-P; Pendergrass, M. and Chen, W., Abst 587-P; Wenten, M. et al., Abst 596-P], whereas in animal models of obesity exenatide rather attenuated or had no impact on experimental pancreatitis [Tatarkiewicz, K. et al., Abst 1627-P; Villescaz, C. et al., Abst 1633-P]. Similarly, use of exenatide was not associated with increased incidence of acute renal failure [Pendergrass, M. and Chen, W., Abst 11-LB].

While oral administration of exenatide was documented feasible with a novel technology [Eldor, R. et al., Abst 6-LB] and a novel continuous subcutaneous delivery proved as effective as twice-daily subcutaneous injection [Cuddihy, R. et al., Abst 7-LB], modification of the exenatide molecule by adding a XTEN peptide to prolong stability and allow for reduced frequency of dosing resulted in VRS-859, which, along with a similar construct with glucagon, showed potential as a treatment for obesity and diabetes in the experimental arena [Cleland, J.L. et al., Abst 617-P]. A further exenatide-based construct with immunoglobulin G Fc fragment also offered benefits by preventing immunogenicity against the compound [Liang, Y. et al., Abst 1652-P].

Favorable pharmacokinetics and tolerability in patients with type 2 diabetes were reported with reduced-dosing albiglutide, supporting the use of weekly or less frequent dosing regimens [Bush, M.A. et al., Abst 598-P].

A more recent drug within this group, taspoglutide proved superior to placebo [Hollander, P. et al., Abst 858-P] and was as effective as exenatide in improving postprandial glucose and glucagon levels, but also significantly increased insulin output in patients with type 2 diabetes [Rosenstock, J. et al., Abst 719-P]. Taspoglutide was as effective as insulin glargine regarding glycemic control in type 2 diabetes pretreated with metformin, but was associated with a lower risk for hypoglycemia and better weight loss [Nauck, M. et al., Abst 60-OR] (Fig. 9and 10). Taspoglutide was superior to sitagliptin [Bergenstal, R. et al., Abst 58-OR] and exenatide [Rosenstock, J. et al., Abst 62-OR] (Fig. 11) according to additional comparative studies, and compared to placebo exerted an insulin-sensitizing effect that was more pronounced on the first-, but was also maintained in the second-phase response [Pellanda, C. et al., Abst 588-P]. In the experimental mechanistic arena, taspoglutide was associated with protective effects on b-cell survival [Uhles, S. et al., Abst 544-P].

Fibrates also have value in the management of dyslipidemia in diabetes, with a marked benefit on postprandial triglyceride levels, as demonstrated with fenofibrate in the ACCORD trial [Reyes-Soffer, G. et al., Abst 1075-P].

The use of an undisclosed somatostatin receptor-2 blocker improved and prevented hypoglycemia in animal models of recurrently hypoglycemic diabetes through an effect on glucagon [Yue, J.T.Y. et al., Abst 754-P].